Valve arrangement for medical device

ABSTRACT

The invention faces the technical problem of reducing the uncertainty over exact doses ejected from a medical device and at the same time providing a homogeneous, but controlled mixture of at least two fluids while a simple production should be maintained. A medical device comprising a first valve, a second valve, a first pre-valve ullage, a second pre-valve ullage, a post-valve ullage with a first end and a second end and a needle is presented. The first pre-valve ullage is connected to the post-valve ullage by the first valve and the second pre-valve ullage is connected to the post-valve ullage by the second valve. A first fluid is guidable from the first pre-valve ullage to the post-valve ullage and a second fluid is guidable from the second pre-valve ullage to the post-valve ullage.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase application pursuant to35 U.S.C. §371 of International Application No. PCT/EP2012/057682 filedApr. 26, 2012, which claims priority to U.S. Provisional PatentApplication No. 61/480,063 filed Apr. 28, 2011, and European PatentApplication No. 11173269.9 filed Jul. 8, 2011. The entire disclosurecontents of these applications are herewith incorporated by referenceinto the present application.

FIELD OF DISCLOSURE

The present patent application relates to medical devices for deliveringat least two drug agents from separate reservoirs. Such drug agents maycomprise a first and a second medicament. The medical device includes adose setting mechanism for delivering the drug agents automatically ormanually by the user.

The medical device can be an injector, for example a hand-held injector,especially a pen-type injector, that is an injector of the kind thatprovides for administration by injection of medicinal products from oneor more multidose cartridges. In particular, the present inventionrelates to such injectors where a user may set the dose.

The drug agents may be contained in two or more multiple dosereservoirs, containers or packages, each containing independent (singledrug compound) or pre-mixed (co-formulated multiple drug compounds) drugagents.

BACKGROUND

Certain disease states require treatment using one or more differentmedicaments. Some drug compounds need to be delivered in a specificrelationship with each other in order to deliver the optimum therapeuticdose. The present patent application is of particular benefit wherecombination therapy is desirable, but not possible in a singleformulation for reasons such as, but not limited to, stability,compromised therapeutic performance and toxicology.

For example, in some cases it may be beneficial to treat a diabetic witha long acting insulin (also may be referred to as the first or primarymedicament) along with a glucagon-like peptide-1 such as GLP-1 or GLP-1analog (also may be referred to as the second drug or secondarymedicament).

Accordingly, there exists a need to provide devices for the delivery oftwo or more medicaments in a single injection or delivery step that issimple for the user to perform without complicated physicalmanipulations of the drug delivery device. The proposed drug deliverydevice provides separate storage containers or cartridge retainers fortwo or more active drug agents. These active drug agents are then onlycombined and/or delivered to the patient during a single deliveryprocedure. These active agents may be administered together in acombined dose or alternatively, these active agents may be combined in asequential manner, one after the other.

SUMMARY

The drug delivery device also allows for the opportunity of varying thequantity of the medicaments. For example, one fluid quantity can bevaried by changing the properties of the injection device (e.g., settinga user variable dose or changing the device's “fixed” dose). The secondmedicament quantity can be changed by manufacturing a variety ofsecondary drug containing packages with each variant containing adifferent volume and/or concentration of the second active agent.

The drug delivery device may have a single dispense interface. Thisinterface may be configured for fluid communication with a primaryreservoir and with a secondary reservoir of medicament containing atleast one drug agent. The drug dispense interface can be a type ofoutlet that allows the two or more medicaments to exit the system and bedelivered to the patient.

The combination of compounds from separate reservoirs can be deliveredto the body via a double-ended needle assembly. This provides acombination drug injection system that, from a user's perspective,achieves drug delivery in a manner that closely matches the currentlyavailable injection devices that use standard needle assemblies. Onepossible delivery procedure may involve the following steps:

1. Attach a dispense interface to a distal end of the electro-mechanicalinjection device. The dispense interface comprises a first and a secondproximal needle. The first and second needles pierce a first reservoircontaining a primary compound and a second reservoir containing asecondary compound, respectively.

2. Attach a dose dispenser, such as a double-ended needle assembly, to adistal end of the dispense interface. In this manner, a proximal end ofthe needle assembly is in fluidic communication with both the primarycompound and secondary compound.

3. Dial up/set a desired dose of the primary compound from the injectiondevice, for example, via a graphical user interface (GUI).

4. After the user sets the dose of the primary compound, themicro-processor controlled control unit may determine or compute a doseof the secondary compound and preferably may determine or compute thissecond dose based on a previously stored therapeutic dose profile. It isthis computed combination of medicaments that will then be injected bythe user. The therapeutic dose profile may be user selectable.Alternatively, the user can dial or set a desired dose of the secondarycompound.

5. Optionally, after the second dose has been set, the device may beplaced in an armed condition. The optional armed condition may beachieved by pressing and/or holding an “OK” or an “Arm” button on acontrol panel. The armed condition may be provided for a predefinedperiod of time during which the device can be used to dispense thecombined dose.

6. Then, the user will insert or apply the distal end of the dosedispenser (e.g., a double ended needle assembly) into the desiredinjection site. The dose of the combination of the primary compound andthe secondary compound (and potentially a third medicament) isadministered by activating an injection user interface (e.g., aninjection button).

Both medicaments may be delivered via one injection needle or dosedispenser and in one injection step. This offers a convenient benefit tothe user in terms of reduced user steps compared to administering twoseparate injections.

Using a single device and especially using a single injection needle toreduce the normally two injection steps to a single step generates theproblem of an uncontrolled mixture of the two drug agents used.

It is always necessary for a successful therapy to deliver the twodifferent drug agents to the patient in a very particular dose. Sincethe two drug agents share a common injection needle the two differentdrug agents need to mix at some point in the medical device, in case thetwo drug agents are administered in a combined dose. Due to thecomparable big volumes and long paths the drug agents need to passbetween the reservoirs and the injection site an uncontrollable mixtureof the medicaments can often not be avoided, producing an uncertainty onthe exact dose administered.

In case the two drug agents are administered in a sequential manner oneafter another, there is also an uncertainty over the exact doseadministered, especially the exact dose of the second drug agent, sincethe fluidic channels in the drug delivery device are of course at leastpartially filled with remainders of the first drug agents, leading againto an uncontrolled mixing of the two medicaments.

The invention faces the technical problem of reducing the uncertaintyover exact doses ejected from a medical device and reducing the risk ofcross-contamination of the two or more medicaments.

The technical problem is solved by a medical device comprising a firstvalve, a second valve, a first pre-valve ullage, a second pre-valveullage, a post-valve ullage with a first end and a second end and aneedle. The first pre-valve ullage is connected to the post-valve ullageby the first valve and the second pre-valve ullage is connected to thepost-valve ullage by the second valve. A first fluid is guidable fromthe first pre-valve ullage to the post-valve ullage and a second fluidis guidable from the second pre-valve ullage to the post-valve ullage. Afirst end of the needle is inserted into the post-valve ullage and thepost-valve ullage is designed such that there is a flow inversionbetween the post-valve ullage and the needle.

By providing two separate valves for each of the at least two fluids,the fluids are kept separate in their own pre-valve ullages. This limitsthe region, where the different fluids can mix, to the post-valveullage. It has been found that this way a much more precise, controlledand predictable mixture of the different fluid, in particular drugagents, can be ejected from the medical device. Of course, the pre-valveullages do not have a direct connection to each other apart from theirconnection to the common post-valve ullage over the respective valves.

The two separate valves for each fluid also prevent the first fluid tobe pushed into the second pre-valve ullage or even further back, forexample into a reservoir for the second fluid and vice versa.

In case the fluids are ejected from the medical device one afteranother, the inventive medical device improves the uncertainty overexact doses, since the common fluidic passage is reduced to thepost-valve ullage. That means that the amount of the first fluidremaining in the common fluidic passage is effectively reduced, thusproviding a better control of the second dose.

The volume of the post-valve ullage though is still sufficient toprovide a region, in which both medicaments can mix sufficiently, sothat a homogeneous mixture of the fluids is provided in case the fluidsare ejected together.

According to another embodiment the medical device further comprises afirst reservoir and a second reservoir, wherein the first reservoir isconnected to the first pre-valve ullage and the second reservoir isconnected to the second pre-valve ullage. These reservoirs provideseparate storage vessels for the first and second fluid. This isparticularly useful for drug agents, which must not be stored togetheror in a ready-made mixture. This way, the fluids, in particular drugagents, mix in the post-valve ullage for the first time, right beforethe mixture is ejected from the medical device and/or injected at theinjection site, for example.

The reservoirs are preferably detachably attached to the respectivepre-valve ullages. This connection can in particular be provided byneedles or cannulas, which are preferably made from metal, for examplesteel. This accounts for the fact, that the reservoirs might beexchanged with different frequencies than the part of the medical devicecontaining said ullages and valves.

The first and second pre-valve ullages can be in constant fluidcommunication with the respective reservoir. The valves prevent thefluids to enter the post-valve ullage while the medical device is notused.

According to another embodiment of the medical device, a first end ofthe needle is inserted into the post-valve ullage at the second end ofthe post-valve ullage. This provides a simple possibility to guideeither fluid or a mixture of both fluids to an injection site. Nofurther guiding by complicated fluidic systems is needed and the overallfluidic system from the reservoir to the injection site, in particularfrom the post-valve ullage to the injection site is minimized. Thisfurther reduces unnecessary volume for the fluids to pass and improvesthe accuracy of the doses. The needle is preferably made of metal, inparticular steel, to provide a biocompatible material and to be able todirectly inject the fluids into the skin of a user, for example.

Such a needle can in particular be a double ended needle, which can beattached to the medical device, providing an exchangeable injectionneedle.

It is further preferred when the first end of the needle issubstantially in the center of the post-valve ullage. On the one hand,this reduces the danger of damaging the post valve ullage with the firstend of the needle.

On the other hand, this provides a flow inversion and thus furtherimproves the flow efficiency. The fluids enter the post-valve ullage,for example at its first end or at its second end, and the fluids exitthe post-valve ullage through the needle in or near the center or at ornear an opposite end of the post-valve ullage. This configuration makesthe fluid change directions and thus provides an excellent mixing of thefluids and an improved flow-out. This effect is especially distinct,when the fluids enter the post-valve ullage at its second end, since theflow directions of the fluids during entering and exiting the post-valveullage are anti-parallel.

According to another embodiment of the medical device, the first fluidand/or the second fluid enter the post-valve ullage substantiallytangentially. That means, if the post valve ullage has a substantiallycylindrical shape for example, the first fluid and/or the second fluidenter the post-valve ullage tangentially to its curved surface area. Inthis way, a particularly effective mixing of the fluids can be achieved.

According to the invention the post-valve ullage is designed such thatthere is a flow inversion between the post valve ullage and the needle.This effect can in particular be achieved by providing a post-valveullage, into which the fluids enter at the second end of the post-valveullage, while the first end of the needle is located in or near thecenter or at or near the first end of the post-valve ullage. Thisresults in the effect that the fluids flow into the post-valve ullagesubstantially from the second end towards the first end of thepost-valve ullage and exit the post-valve ullage through the first endof the needle flowing substantially from the first end of the post valveullage in the direction of the second end of the post valve ullage.Thus, an antiparallel upward and downward movement of the fluidsprovides in this case the flow inversion and therefore an effectivemixing of the fluids.

The same effect is achieved in case the fluids enter the post valveullage at the first end of the post-valve ullage for example, since atleast a part of the fluids will reach the second end of the post-valveullage and the fluids will have to flow towards the first end of thepost-valve ullage to reach the center of the post-valve ullage and toexit through the first end of the needle. Thus, a flow inversion isachieved in the post-valve ullage and a particularly effective mixing ofthe fluids can be achieved.

According to another embodiment of the medical device, it isadvantageous, when the first pre-valve ullage and the second pre-valveullage are provided by an inner body and the first valve and the secondvalve are provided by a first and a second elastic part respectivelyadjacent to an outer body of the medical device.

This facilitates the production of the medical device. The valve isprovided between outer and inner body, such that no stand-alone partsare necessary in this arrangement as for example for diaphragm valves.The first and second elastic parts seal the fluidic connection betweenthe respective pre-valve ullages and the post-valve ullage.

Preferably, the elastic parts have flexible portions such that theflexible portions can move freely and the valves are opened and closeddepending on the pressure of the respective fluids in the pre-valveullages. If the pressure is high enough in the first pre-valve ullage,the flexible portion is preferably pushed out of the way opening thefirst valve and establishing a fluid connection between the firstpre-valve ullage and the post valve ullage. The second valve can work inthe same way. Though, it is also possible that the valves are activatedautomatically by a mechanical mechanism, for example.

Preferably the valves are of such design, that the valve is a one wayvalve and a backpressure from the post-valve ullage cannot open thevalves.

Such a so called “sleeve valve” can be easily implemented by a circulardiaphragm valve, for example.

The elastic part might also be designed integrally with the outer bodyof the medical device.

It is preferred, when the post-valve ullage is configured such that thefluid enters the post-valve ullage at the second end of the post valveullage. The fluid can be guided to the second end of the post-valveullage by fluidic channels connecting the respective valve with thesecond end of the post-valve ullage. This way a more homogenous mixingof the fluids can be achieved and an efficient guiding of the fluidswith a minimal length of the fluidic system, since the fluids do notneed to be guided to the first end of the post-valve ullage again. Thisfurther promotes the reduction of the uncertainty over exact dosesejected, while at the same time a homogeneous, but controlled mixture isprovided.

According to another embodiment of the Medical device, the first valveand the second valve are provided by valves located at the first end ofthe post-valve ullage. This arrangement provides a minimal channellength from the pre-valve ullages or the reservoirs to the post-valveullage or the injection site. This further reduces the uncertainty overexact doses ejected from the medical device and at the same timeprovides a homogeneous, but controlled mixture of two fluids.

The valves can be designed as standard umbrella or diaphragm valves, butmay preferably be designed as so called “beak valves”. Such beak valvesare substantially funnel shaped with a point-shaped opening or anopening in form of a slit. In the closed state the elastic materialadjacent to the opening is pre-stressed such that the opening is closed.The pressure of the fluid can open force the elastic material aside, sothat the beak valve opens.

It is especially preferred, when the first valve is configured to becontrolled by the pressure of the fluid in the first pre-valve ullageand/or the second valve is configured to be controlled by the pressureof the fluid in the second pre-valve ullage. This provides a very simpleand cost-sensitive implementation of the valves into the medical device,because no external control of the valves is necessary, for example bymechanical actuators or the like.

It is especially preferred when the first valve and/or the second valveis at least in part made from one or more materials selected from thegroup of TPE, PTFE, silicone and EPDM. These materials are especiallysuitable since they show a high biocompatibility, for examplerequirements for sterilization, and at the same time provide asufficient sealing function between the pre-valve ullage and thepost-valve ullage.

Valves from thermoplastic elastomers (TPE) are especially easy toproduce since they can be molded and only little or no compounding isnecessary to achieve the desired material properties.

Polytetrafluoroethylene (PTFE) shows a very low coefficient of frictionoptimizing the fluidic properties of the medical device. Moreover PTFEis subjected to material creep, which can be advantageous when used invalves and seals, since the valve or seal creeps a certain amount andcan thus match the corresponding counter-surface to establish a tightseal.

Silicone is readily tested in medical appliances and provides goodsealing properties combined with good biocompatibility.

Valves made from ethylene propylene diene monomer rubber (EPDM) providea high resistivity against humidity and ozone. Furthermore EPDM has ahigh chemical stability and a high elasticity, providing excellentproperties for sealing applications.

In particular the medical device is a drug delivery system. Especiallyfor drug delivery systems it is of utmost importance to reduce theuncertainty over exact doses ejected and at the same time providing ahomogeneous, but controlled mixture of the ejected fluids.

It is especially advantageous if the medical device further comprises adispense interface comprising the first valve, the second valve, thefirst pre-valve ullage, the second pre-valve ullage and the post-valveullage with the first end and said second end. The dispense interfacecan hence be exchanged or replaced independently from the rest of themedical device, especially a cartridge holder, containing the first andsecond reservoir.

BRIEF DESCRIPTION OF THE FIGURES

These as well as other advantages of various aspects of the presentinvention will become apparent to those of ordinary skill in the art byreading the following detailed description, with appropriate referenceto the accompanying drawings, in which:

FIG. 1 illustrates a perspective view of a delivery device with an endcap of the device removed;

FIG. 2 illustrates a perspective view of the delivery device distal endshowing the cartridge;

FIG. 3 illustrates a perspective view of the delivery device illustratedin FIG. 1 or 2 with one cartridge retainer in an open position;

FIG. 4 illustrates a dispense interface and a dose dispenser that may beremovably mounted on a distal end of the delivery device illustrated inFIG. 1;

FIG. 5 illustrates the dispense interface and the dose dispenserillustrated in FIG. 4 mounted on a distal end of the delivery deviceillustrated in FIG. 1;

FIG. 6 illustrates a needle assembly that may be mounted on a distal endof the delivery device;

FIG. 7 illustrates a perspective view of the dispense interfaceillustrated in FIG. 4;

FIG. 8 illustrates another perspective view of the dispense interfaceillustrated in FIG. 4;

FIG. 9 illustrates an exemplary embodiment of the invention in across-sectional view of the dispense interface illustrated in FIG. 4;

FIG. 10 illustrates an exploded view of the dispense interfaceillustrated in FIG. 4;

FIG. 11 illustrates a cross-sectional view of the dispense interface andneedle assembly mounted onto a drug delivery device, such as the deviceillustrated in FIG. 1;

FIG. 12 illustrates another exemplary embodiment according to theinvention in a cross sectional view;

FIG. 13 illustrates another exemplary embodiment according to theinvention in a cross sectional view.

DETAILED DESCRIPTION

The drug delivery device illustrated in FIG. 1 comprises a main body 14that extends from a proximal end 16 to a distal end 15. At the distalend 15, a removable end cap or cover 18 is provided. This end cap 18 andthe distal end 15 of the main body 14 work together to provide a snapfit or form fit connection so that once the cover 18 is slid onto thedistal end 15 of the main body 14, this frictional fit between the capand the main body outer surface 20 prevents the cover from inadvertentlyfalling off the main body.

The main body 14 contains a micro-processor control unit, anelectro-mechanical drive train, and at least two medicament reservoirs.When the end cap or cover 18 is removed from the device 10 (asillustrated in FIG. 1), a dispense interface 200 is mounted to thedistal end 15 of the main body 14, and a dose dispenser (e.g., a needleassembly) is attached to the interface. The drug delivery device 10 canbe used to administer a computed dose of a second medicament (secondarydrug compound) and a variable dose of a first medicament (primary drugcompound) through a single needle assembly, such as a double endedneedle assembly.

The drive train may exert a pressure on the bung of each cartridge,respectively, in order to expel the doses of the first and secondmedicaments. For example, a piston rod may push the bung of a cartridgeforward a pre-determined amount for a single dose of medicament. Whenthe cartridge is empty, the piston rod is retracted completely insidethe main body 14, so that the empty cartridge can be removed and a newcartridge can be inserted.

A control panel region 60 is provided near the proximal end of the mainbody 14. Preferably, this control panel region 60 comprises a digitaldisplay 80 along with a plurality of human interface elements that canbe manipulated by a user to set and inject a combined dose. In thisarrangement, the control panel region comprises a first dose settingbutton 62, a second dose setting button 64 and a third button 66designated with the symbol “OK.” In addition, along the most proximalend of the main body, an injection button 74 is also provided (notvisible in the perspective view of FIG. 1).

The cartridge holder 40 can be removably attached to the main body 14and may contain at least two cartridge retainers 50 and 52. Eachretainer is configured so as to contain one medicament reservoir, suchas a glass cartridge. Preferably, each cartridge contains a differentmedicament.

In addition, at the distal end of the cartridge holder 40, the drugdelivery device illustrated in FIG. 1 includes a dispense interface 200.As will be described in relation to FIG. 4, in one arrangement, thisdispense interface 200 includes a main outer body 212 that is removablyattached to a distal end 42 of the cartridge housing 40. As can be seenin FIG. 1, a distal end 214 of the dispense interface 200 preferablycomprises a needle hub 216. This needle hub 216 may be configured so asto allow a dose dispenser, such as a conventional pen type injectionneedle assembly, to be removably mounted to the drug delivery device 10.

Once the device is turned on, the digital display 80 shown in FIG. 1illuminates and provides the user certain device information, preferablyinformation relating to the medicaments contained within the cartridgeholder 40. For example, the user is provided with certain informationrelating to both the primary medicament (Drug A) and the secondarymedicament (Drug B).

As shown in FIG. 3, the first and second cartridge retainers 50, 52 maybe hinged cartridge retainers. These hinged retainers allow user accessto the cartridges. FIG. 3 illustrates a perspective view of thecartridge holder 40 illustrated in FIG. 1 with the first hingedcartridge retainer 50 in an open position. FIG. 3 illustrates how a usermight access the first cartridge 90 by opening up the first retainer 50and thereby having access to the first cartridge 90.

As mentioned above when discussing FIG. 1, a dispense interface 200 iscoupled to the distal end of the cartridge holder 40. FIG. 4 illustratesa flat view of the dispense interface 200 unconnected to the distal endof the cartridge holder 40. A dose dispenser or needle assembly 400 thatmay be used with the interface 200 is also illustrated and is providedin a protective outer cap 420.

In FIG. 5, the dispense interface 200 illustrated in FIG. 4 is showncoupled to the cartridge holder 40. The axial attachment means betweenthe dispense interface 200 and the cartridge holder 40 can be any knownaxial attachment means to those skilled in the art, including snaplocks, snap fits, snap rings, keyed slots, and combinations of suchconnections. The connection or attachment between the dispense interfaceand the cartridge holder may also contain additional features (notshown), such as connectors, stops, splines, ribs, grooves, pips, clipsand the like design features, that ensure that specific hubs areattachable only to matching drug delivery devices. Such additionalfeatures would prevent the insertion of a non-appropriate secondarycartridge to a non-matching injection device.

FIG. 5 also illustrates the needle assembly 400 and protective cover 420coupled to the distal end of the dispense interface 200 that may bescrewed onto the needle hub of the interface 200. FIG. 6 illustrates across sectional view of the double ended needle assembly 402 mounted onthe dispense interface 200 in FIG. 5.

The needle assembly 400 illustrated in FIG. 6 comprises a double endedneedle 406 and a hub 401. The double ended needle or cannula 406 isfixedly mounted in a needle hub 401. This needle hub 401 comprises acircular disk shaped element which has along its periphery acircumferential depending sleeve 403. Along an inner wall of this hubmember 401, a thread 404 is provided. This thread 404 allows the needlehub 401 to be screwed onto the dispense interface 200 which, in onepreferred arrangement, is provided with a corresponding outer threadalong a distal hub. At a center portion of the hub element 401 there isprovided a protrusion 402. This protrusion 402 projects from the hub inan opposite direction of the sleeve member. A double ended needle 406 ismounted centrally through the protrusion 402 and the needle hub 401.This double ended needle 406 is mounted such that a first or distalpiercing end 405 of the double ended needle forms an injecting part forpiercing an injection site (e.g., the skin of a user).

Similarly, a second or proximal piercing end 406 of the needle assembly400 protrudes from an opposite side of the circular disc so that it isconcentrically surrounded by the sleeve 403. In one needle assemblyarrangement, the second or proximal piercing end 406 may be shorter thanthe sleeve 403 so that this sleeve to some extent protects the pointedend of the back sleeve. The needle cover cap 420 illustrated in FIGS. 4and 5 provides a form fit around the outer surface 403 of the hub 401.

Referring now to FIGS. 4 to 11, one preferred arrangement of thisinterface 200 will now be discussed. In this one preferred arrangement,this interface 200 comprises:

a. a main outer body 210,

b. an first inner body 220,

c. a second inner body 230,

d. a first piercing needle 240,

e. a second piercing needle 250,

f. a valve seal 260, and

g. a septum 270.

The main outer body 210 comprises a main body proximal end 212 and amain body distal end 214. At the proximal end 212 of the outer body 210,a connecting member is configured so as to allow the dispense interface200 to be attached to the distal end of the cartridge holder 40.Preferably, the connecting member is configured so as to allow thedispense interface 200 to be removably connected the cartridge holder40. In one preferred interface arrangement, the proximal end of theinterface 200 is configured with an upwardly extending wall 218 havingat least one recess. For example, as may be seen from FIG. 8, theupwardly extending wall 218 comprises at least a first recess 217 and asecond recess 219.

Preferably, the first and the second recesses 217, 219 are positionedwithin this main outer body wall so as to cooperate with an outwardlyprotruding member located near the distal end of the cartridge housing40 of the drug delivery device 10. For example, this outwardlyprotruding member 48 of the cartridge housing may be seen in FIGS. 4 and5. A second similar protruding member is provided on the opposite sideof the cartridge housing. As such, when the interface 200 is axiallyslid over the distal end of the cartridge housing 40, the outwardlyprotruding members will cooperate with the first and second recess 217,219 to form an interference fit, form fit, or snap lock. Alternatively,and as those of skill in the art will recognize, any other similarconnection mechanism that allows for the dispense interface and thecartridge housing 40 to be axially coupled could be used as well.

The main outer body 210 and the distal end of the cartridge holder 40act to form an axially engaging snap lock or snap fit arrangement thatcould be axially slid onto the distal end of the cartridge housing. Inone alternative arrangement, the dispense interface 200 may be providedwith a coding feature so as to prevent inadvertent dispense interfacecross use. That is, the inner body of the hub could be geometricallyconfigured so as to prevent an inadvertent cross use of one or moredispense interfaces.

A mounting hub is provided at a distal end of the main outer body 210 ofthe dispense interface 200. Such a mounting hub can be configured to bereleasably connected to a needle assembly. As just one example, thisconnecting means 216 may comprise an outer thread that engages an innerthread provided along an inner wall surface of a needle hub of a needleassembly, such as the needle assembly 400 illustrated in FIG. 6.Alternative releasable connectors may also be provided such as a snaplock, a snap lock released through threads, a bayonet lock, a form fit,or other similar connection arrangements.

The dispense interface 200 further comprises a first inner body 220.Certain details of this inner body are illustrated in FIG. 8-11.Preferably, this first inner body 220 is coupled to an inner surface 215of the extending wall 218 of the main outer body 210. More preferably,this first inner body 220 is coupled by way of a rib and groove form fitarrangement to an inner surface of the outer body 210. For example, ascan be seen from FIG. 9, the extending wall 218 of the main outer body210 is provided with a first rib 213 a and a second rib 213 b. Thisfirst rib 213 a is also illustrated in FIG. 10. These ribs 213 a and 213b are positioned along the inner surface 215 of the wall 218 of theouter body 210 and create a form fit or snap lock engagement withcooperating grooves 224 a and 224 b of the first inner body 220. In apreferred arrangement, these cooperating grooves 224 a and 224 b areprovided along an outer surface 222 of the first inner body 220.

In addition, as can be seen in FIG. 8-10, a proximal surface 226 nearthe proximal end of the first inner body 220 may be configured with atleast a first proximally positioned piercing needle 240 comprising aproximal piercing end portion 244. Similarly, the first inner body 220is configured with a second proximally positioned piercing needle 250comprising a proximally piercing end portion 254. Both the first andsecond needles 240, 250 are rigidly mounted on the proximal surface 226of the first inner body 220.

Preferably, this dispense interface 200 further comprises a valvearrangement. The valve arrangement is constructed so as to prevent crosscontamination of the first and second medicaments contained in the firstand second reservoirs, respectively. Additionally, the valve arrangementis also configured so as to prevent back flow and cross contamination ofthe first and second medicaments.

In one preferred system, dispense interface 200 includes a valvearrangement in the form of a valve seal 260. Such a valve seal 260 maybe provided within a cavity 231 defined by the second inner body 230, soas to form a holding chamber 280. Preferably, cavity 231 resides alongan upper surface of the second inner body 230. This valve seal comprisesan upper surface that defines both a first fluid groove or a firstpre-valve ullage 264 and second fluid groove or a second pre-valveullage 266. For example, FIG. 9 illustrates the position of the valveseal 260, seated between the first inner body 220 and the second innerbody 230. During an injection step, this seal valve 260 helps to preventthe primary medicament in the first pathway from migrating to thesecondary medicament in the second pathway, while also preventing thesecondary medicament in the second pathway from migrating to the primarymedicament in the first pathway. This seal valve 260 comprises a firstnon-return valve 262 and a second non-return valve 268. As such, thefirst non-return valve 262 prevents fluid transferring along the firstfluid pathway or first pre-valve ullage 264, for example a groove in theseal valve 260, from returning back into this pathway or pre-valveullage 264. Similarly, the second non-return valve or second pre-valveullage 268 prevents fluid transferring along the second fluid pathway orsecond pre-valve ullage 266 from returning back into this pathway orpre-valve ullage 266.

Together, the first and second grooves or pre-valve ullages 264, 266converge towards the non-return valves 262 and 268 respectively, to thenprovide for an output fluid path or a post-valve ullage in form of aholding chamber 280. This holding chamber 280 is defined by an innerchamber defined by a distal end of the second inner body, a first end281 with both the first and the second non return valves 262, 268 and asecond end 282 with a pierceable septum 270. As illustrated, thispierceable septum 270 is positioned between a distal end portion of thesecond inner body 230 and an inner surface defined by the needle hub ofthe main outer body 210.

The holding chamber or post-valve ullage 280 terminates at an outletport of the interface 200. This outlet port 290 is preferably centrallylocated in the needle hub of the interface 200 and assists inmaintaining the pierceable seal 270 in a stationary position. As such,when a double ended needle assembly is attached to the needle hub of theinterface (such as the double ended needle illustrated in FIG. 6), theoutput fluid path allows both medicaments to be in fluid communicationwith the attached needle assembly.

The hub interface 200 further comprises a second inner body 230. As canbe seen from FIG. 9, this second inner body 230 has an upper surfacethat defines a recess, and the valve seal 260 is positioned within thisrecess. Therefore, when the interface 200 is assembled as shown in FIG.9, the second inner body 230 will be positioned between a distal end ofthe outer body 210 and the first inner body 220. Together, second innerbody 230 and the main outer body hold the septum 270 in place. Thedistal end of the inner body 230 may also form a cavity or holdingchamber that can be configured to be fluid communication with both thefirst groove or first pre-valve ullage 264 and the second groove orsecond pre-valve ullage 266 of the valve seal.

Axially sliding the main outer body 210 over the distal end of the drugdelivery device attaches the dispense interface 200 to the multi-usedevice. In this manner, a fluid communication may be created between thefirst needle 240 and the second needle 250 with the primary medicamentof the first cartridge and the secondary medicament of the secondcartridge, respectively.

FIG. 11 illustrates the dispense interface 200 after it has been mountedonto the distal end 42 of the cartridge holder 40 of the drug deliverydevice 10 illustrated in FIG. 1. A double ended needle 400 is alsomounted to the distal end of this interface. The cartridge holder 40 isillustrated as having a first cartridge containing a first medicamentand a second cartridge containing a second medicament.

When the interface 200 is first mounted over the distal end of thecartridge holder 40, the proximal piercing end 244 of the first piercingneedle 240 pierces the septum of the first cartridge 90 and therebyresides in fluid communication with the primary medicament 92 of thefirst cartridge 90. A distal end of the first piercing needle 240 willalso be in fluid communication with a first fluid path groove 264defined by the valve seal 260.

Similarly, the proximal piercing end 254 of the second piercing needle250 pierces the septum of the second cartridge 100 and thereby residesin fluid communication with the secondary medicament 102 of the secondcartridge 100. A distal end of this second piercing needle 250 will alsobe in fluid communication with a second fluid path groove 266 defined bythe valve seal 260.

FIG. 11 illustrates a preferred arrangement of such a dispense interface200 that is coupled to a distal end 15 of the main body 14 of drugdelivery device 10. Preferably, such a dispense interface 200 isremovably coupled to the cartridge holder 40 of the drug delivery device10.

As illustrated in FIG. 11, the dispense interface 200 is coupled to thedistal end of a cartridge housing 40. This cartridge holder 40 isillustrated as containing the first cartridge 90 containing the primarymedicament 92 and the second cartridge 100 containing the secondarymedicament 102. Once coupled to the cartridge housing 40, the dispenseinterface 200 essentially provides a mechanism for providing a fluidcommunication path from the first and second cartridges 90, 100 to thecommon holding chamber 280. This holding chamber or post-valve ullage280 is illustrated as being in fluid communication with a dosedispenser. Here, as illustrated, this dose dispenser comprises thedouble ended needle assembly 400. As illustrated, the proximal end ofthe double ended needle assembly is in fluid communication with theullage 280.

In one preferred arrangement, the dispense interface is configured sothat it attaches to the main body in only one orientation, that is it isfitted only one way round. As such as illustrated in FIG. 11, once thedispense interface 200 is attached to the cartridge holder 40, theprimary needle 240 can only be used for fluid communication with theprimary medicament 92 of the first cartridge 90 and the interface 200would be prevented from being reattached to the holder 40 so that theprimary needle 240 could now be used for fluid communication with thesecondary medicament 102 of the second cartridge 100. Such a one wayaround connecting mechanism may help to reduce potential crosscontamination between the two medicaments 92 and 102.

In an alternative valve arrangement, the dispense interface may comprisea valve arrangement comprising a sleeve valve arrangement. For example,FIG. 12 illustrates a cross sectional view of an alternative valvearrangement for use in a dispense interface 200. In this arrangement,the dispense interface 300 comprises a sleeve valve arrangement 302.

As illustrated, the dispense interface 300 comprises a first medicamentpre-valve ullage 304 and a second medicament pre-valve ullage 306. Thefirst medicament pre-valve ullage 304 would contain ullage of the firstmedicament residing between the cartridge containing the firstmedicament and the first medicament valve 308. Similarly, the secondmedicament pre-valve ullage 306 would contain ullage of the secondmedicament residing between the cartridge containing the secondmedicament and the second medicament valve 310.

As in the areas of 308 and 310, the flexible portion of the elastic partis not jacked up by the outer housing of the dispense interface 300. Assuch, these flexible portions are free to flexibly move and are drivenby pressure/backpressure, similar to the valve arrangement illustratedin FIG. 9. The flexible portions are connected to the rest of theelastic component and, in this arrangement, do not comprise stand-alonecomponents other solutions in the state of the art.

The post valve ullage 312 is provided as a holding chamber 314 of thedispense interface 300. In this arrangement, both the first and thesecond cartridges contained within the drug delivery device comprisetheir own one-way valve that connect to a shared post valve ullage. Oncea dispenser, such as a double ended needle assembly, is mounted to thedistal end of the dispense interface, the shared post valve ullage wouldbe in fluid communication with this dispenser acting as an outletneedle.

The post-valve ullage 312 has a first end 316 and a second end 318. Inthis embodiment the medicaments enter the post-valve ullage 312 throughthe second end 318. The end of a double ended needle 406 can be insertedthrough the same end 318.

As can be further seen from FIG. 12, the ullages are provided by theinner body 320, while the valves are positioned between the inner body320 and the outer body 322. Here, the drug agents 92, 102 are guidedpast the post-valve ullage 312 to be inserted into the post-valve ullage312 at the second end 318 of the post-valve ullage 312. A needle 406 asillustrated in FIG. 13 is usually already inserted in to the post valveullage 312. This results in the effect that the drug agents 92, 102 flowinto the post-valve ullage 312 substantially from the second end 318towards the first end 316 of the post valve ullage 312 and exit thepost-valve ullage 312 through the first end 405 of the needle 406substantially from the first end 316 of the post valve ullage 312 in thedirection of the second end 318 of the post valve ullage 312. Thus, aflow inversion is achieved in the post-valve ullage 312 and aparticularly effective mixing of the drug agents 92, 102 can beachieved.

Alternatively, the dispense interface may comprise a valve arrangementcomprising a beak valve arrangement. For example, FIG. 13 illustrates across sectional view of a beak valve arrangement 502 for use in adispense interface 500. As illustrated, the dispense interface 500comprises a first medicament pre-valve ullage 504 and a secondmedicament pre-valve ullage 506. In this arrangement, both the first andthe second cartridges contained within the drug delivery device comprisea separate own one-way valve. For example, the first cartridgecontaining the primary medicament would comprise the first one-way valve508 and the second cartridge containing the secondary medicament wouldcontain the second one-way valve 510. In this arrangement, both thefirst and the second cartridges contained within the drug deliverydevice comprise their own one-way valve that connect to a shared postvalve ullage 512 in form of a holding chamber 514. Once a doser, such asa double ended needle assembly, is mounted to the distal end of thedispense interface, the shared post valve ullage would be in fluidcommunication with this dispenser acting as an outlet needle.

In this case the drug agents enter the post-valve ullage 512 through thefirst end 516. As can be further seen from FIG. 13, the first end 407 ofthe needle 406 is positioned substantially in the middle of thepost-valve ullage 512. Thus, while the drug agents 92, 102 enter thepost valve ullage 512 at the first end 516 of the post-valve ullage 512and at least a part of the drug agents 92, 102 will reach the second end518 of the post-valve ullage 512, the drug agents 92, 102 have to exitthrough the first end 405 of the needle 406 and therefore will have toflow again towards the first end 516 of the post-valve ullage 512 toreach the center of the post-valve ullage 512. Thus, a flow inversion isachieved in the post-valve ullage 512 and a particularly effectivemixing of the drug agents 92, 102 can be achieved.

In particular the valves 308, 310, 508, 510 illustrated in FIGS. 12 and13, can be made of a material such as TPE, PTFE, silicone or EPDM.

The term “drug” or “medicament”, as used herein, means a pharmaceuticalformulation containing at least one pharmaceutically active compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exedin-3 or exedin-4 or an analogue or derivative ofexedin-3 or exedin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyhepta-decanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence HHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

-   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),    wherein the group -Lys6-NH2 may be bound to the C-terminus of the    Exendin-4 derivative;    or an Exendin-4 derivative of the sequence-   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,-   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]    Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(S1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2;    or a pharmaceutically acceptable salt or solvate of any one of the    afore-mentioned Exedin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystallizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H—H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

1-12. (canceled)
 13. Medical device comprising: a first valve, a secondvalve, a first pre-valve ullage, a second pre-valve ullage, a post-valveullage with a first end and a second end, and a needle, wherein saidfirst pre-valve ullage is connected to said post-valve ullage by saidfirst valve, wherein said second pre-valve ullage is connected to saidpost-valve ullage by said second valve, wherein a first fluid isguidable from the first pre-valve ullage to the post-valve ullage,wherein a second fluid (102) is guidable from the second pre-valveullage to the post-valve ullage, wherein a first end of said needle isinserted into said post-valve ullage and wherein said post-valve ullageis designed such that there is a flow inversion between said post-valveullage and said needle.
 14. Medical device according to claim 13,further comprising a first reservoir and a second reservoir, whereinsaid first reservoir is connected to said first pre-valve ullage andsaid second reservoir is connected to said second pre-valve ullage. 15.Medical device according to claim 13, wherein a first end of said needleis inserted into said post-valve ullage at the second end of thepost-valve ullage.
 16. Medical device according to claim 13, whereinsaid first end of said needle is substantially in the center of saidpost-valve ullage.
 17. Medical device according to claim 13, wherein thefirst fluid and/or the second fluid enter the post-valve ullagesubstantially tangentially.
 18. Medical device according to claim 13,wherein said first pre-valve ullage and said second pre-valve ullage areprovided by an inner body and said first valve and said second valve areprovided by a first elastic part and a second elastic part adjacent toan outer body of said medical device.
 19. Medical device according toclaim 13, wherein said post-valve ullage is configured such that saidfluid enters the post-valve ullage at the second end of said post valveullage.
 20. Medical device according to claim 13, wherein said firstvalve and said second valve are provided by valves located at the firstend of the post-valve ullage.
 21. Medical device according to claim 13,wherein said first valve is configured to be controlled by the pressureof said fluid in said first pre-valve ullage and/or said second valve isconfigured to be controlled by the pressure of said fluid in said secondpre-valve ullage.
 22. Medical device according to claim 13, wherein thefirst valve and/or the second valve is at least in part made from one ormore materials selected from the group of TPE, PTFE, silicone and EPDM.23. Medical device according to claim 13, wherein said medical device isa drug delivery system.
 24. Medical device according to claim 13,further comprising a dispense interface comprising said first valve,said second valve, said first pre-valve ullage, said second pre-valveullage and said post-valve ullage with said first end and said secondend.